Tendon injuries affect millions of Americans in both occupational and athletic settings and cost billions of healthcare dollars every year. While mechanical loading is considered as a major causative factor responsible for tendon injuries, the molecular mechanisms that initiate translation of mechanical loading into tendon injuries remain unknown. In this study, we offer an innovative hypothesis that HMGB1, a well-established inflammation-related nuclear binding protein in major tissues and organs, is responsible for the onset of the tendon inflammatory cascade due to excessive mechanical loading placed on tendons. Specifically, we propose two aims in this study: 1) to determine the effects of various mechanical loading conditions on tendon cells using a novel in vitro model system; and 2) to determine the effects of mechanical over-loading conditions on mouse tendons in vivo using a well-established mouse treadmill running model. Cellular and molecular analyses will be performed to define the HMGB1 signaling cascade. This study represents the first efforts to determine the role of HMGB1 in the onset of tendon injuries. The successful completion of this study will reveal the early signaling mechanism that is responsible for the development of full blown tendinopathy often seen down-the-road in tendinopathic patients. This research endeavor will lead to new prevention and treatment strategies such as targeting HMGB1 by blocking its action that will be more effective than current tendinopathy treatment options, which are largely palliative.